Significance If early, short-term PMPA therapy in SIV-infected monkeys were able to reducevirus levels, permanently or even transiently, this would support anti-HIV drug treatment as soon as HIV infection is detected by any test. Because the cost of short-term anti-HIV drug therapy would be lower than chronic therapy, short-term drug therapy would be more economically feasible to use, especially in developing nations. Objectives To evaluate the efficacy of short-term treatment with a potent inhibitor of SIV and HIV reverse transcriptase, PMPA, using the simian immunodeficiency virus (SIV)/monkey model of oral-genital HIV-infection. The study tested whether PMPA given to monkeys soon after oral SIV infection could reduce virus levels and delay simian AIDS. Results Fourteen juvenile rhesus were inoculated orally with SIV and all animals became infected. Seven days after SIV inoculation (pi), six of the 14 SIV-infected macaques were treated once daily with PMPA (30 mg/kg, subcutaneously) for 14 days; eight animals were untreated. Seven of the eight untreated animals developed persistent high levels of SIV in their plasma and were euthanized with clinical AIDS by 24 weeks pi. In contrast, all PMPA-treated animals developed no clinical signs of immunodeficiency during the 24 week study. Levels of infectious virus in peripheral blood were reduced up to 1,000-fold in five of the six animals during the two week PMPA treatment. By 5 weeks after PMPA therapy stopped, virus levels in peripheral blood cells of PMPA-treated monkeys had risen 10- to 100-fold from the lowest level achieved during PMPA therapy. Thus, early short-term PMPA treatment can reduce plasma viremia and/or delay disease in juvenile rhesus macaques infected by oral SIV inoculation. Future Directions Additional studies with SIV-infected rhesus will be performed to determine the effects of combining short-term PMPA treatment with vaccination against oral SIV infection. KEYWORDS SIV, AIDS, antiretroviral therapy, PMPA, HIV oral-genital transmission